PROJECT ABSTRACT Chimeric Inhibitors of Androgen Biosynthesis and Signaling Androgens drive the progression of over 80% of prostate cancer tumors. Therefore, treatment strategies often use surgical or chemical castration to disrupt the signaling of these steroid hormones through the androgen receptor (AR). Despite the initial efficacy of such therapies, patients inevitably develop resistance leading to castration-resistant prostate cancer (CRPC), which is sustained by very low androgen levels in the body. Of the few drugs approved for this advanced and fatal stage of the disease, the prodrug abiraterone acetate is the only one designed to target cytochrome P450 17A1 (CYP17A1), an enzyme required for androgen production. In patients, abiraterone (the primary active agent) is converted into the more potent ?4-abiraterone, which both inhibits CYP17A1 and antagonizes the AR. Unfortunately, ?4-abiraterone does not significantly accumulate in patients. Instead, this metabolite is irreversibly modified by 5?-reductase into an AR agonist, which actually promotes prostate cancer cell growth (similar to endogenous androgens). In order to address this immediate medical need, the goal of this proposal is to design analogues of ?4-abiraterone that avoid unwanted metabolism by 5?-reductase but still interrupt androgen biosynthesis and signaling at multiple points. To this end, the immediate objective is to replace the key metabolic liability of ?4-abiraterone, while maintaining potency and enhancing selectivity at CYP17A1, one of the primary drug targets. Accordingly, the following aims will be pursued: (1a) replace the key metabolic liability of ?4-abiraterone, (1b) improve the selectivity of synthesized analogues for CYP17A1, and (2) explore 3-pyridyl substituent effects on the polypharmacology of ?4-abiraterone. The compounds described in this proposal are also designed to inhibit 5?-reductase and antagonize the AR, which is expected to lead to greater anti-tumor activity than ?4-abiraterone itself. In collaboration with researchers from the University of Michigan-Ann Arbor and the University of North Carolina at Chapel Hill, some of the polypharmacology of the proposed compounds will be characterized against key drug targets of CRPC (i.e., CYP17A1, 5?-reductase, and the AR). If the immediate objective is achieved, this research project would demonstrate that mimics of the more potent ?4-abiraterone can be rationally designed, facilitating the development of more effective treatments for advanced stage prostate cancer.